Lamin A/C loss promotes R-loop-mediated genomic instability and poor survival in small-cell lung cancer
Cette étude met en évidence un mécanisme par lequel la perte d'expression des lamines A et C, des composants structurels de l'enveloppe nucléaire, favorise l'instabilité génomique et la progression des cancers du poumon à petites cellules
Lamin A/C, a key structural component of the nuclear envelope, is frequently lost or mutated in cancer, laminopathies, and aging-related disorders. We show that LMNA loss disrupts nuclear pore complex organization and impairs RNA export, leading to R-loop accumulation, replication stress, and genome instability. These findings uncover a mechanistic link between LMNA deficiency, nuclear envelope dysfunction, and genome instability. Targeting this pathway may mitigate genomic instability in aging and laminopathies, while leveraging R-loop accumulation could enhance therapies that exploit replication stress. Lamin A/C (LMNA), a key component of the nuclear envelope, is essential for maintaining nuclear integrity and genome organization [W. Xie et al., Curr. Biol. 26, 2651–2658 (2016)]. While LMNA dysregulation has been implicated in genomic instability across cancer and aging, the underlying mechanisms remain poorly understood [S. Graziano et al., Nucleus 9, 258–275 (2018)]. Here, we define a mechanistic role for LMNA in preserving genome stability in small-cell lung cancer (SCLC), a malignancy marked by extreme genomic instability [N. Takahashi et al., Cancer Res. Commun. 2, 503–517 (2022)]. LMNA depletion promotes R-loop accumulation, transcription-replication conflicts, replication stress, DNA breaks, and micronuclei formation. Mechanistically, LMNA deficiency disrupts nuclear pore complex organization, specifically reducing phenylalanine-glycine (FG)-nucleoporin incorporation, resulting in impaired RNA export and nuclear retention of RNA. LMNA expression is repressed by EZH2 and reexpressed during SCLC differentiation from neuroendocrine (NE) to non-NE states, and low LMNA levels correlate with poor clinical outcomes. These findings establish LMNA as a key regulator of nuclear transport and genome integrity, linking nuclear architecture to SCLC progression and therapeutic vulnerability.
Proceedings of the National Academy of Sciences , résumé, 2025